DESCRIPTION: (Verbatim) Each year 1/2,000 infants is born with a serious skin or skin appendage defect and many more are diagnosed with skin anomalies in the first six months of life. Many of these defects result from mutations in genes required for regulating the carefully choreographed, bi-directional signaling cascades between embryonic dermis and epidermis that is necessary for normal skin development. Our data indicate that complex interactions between the regulatory genes Engrailed- (En 1), Wnt7a and Lmxlb are critical for normal nail and eccrine gland development. More specifically, Eni appears to function at three stages of appendage development: patterning, morphogenesis and differentiation. We propose to: 1. To provide a foundation for our mutant studies by delineating the normal steps of eccrine gland and nail morphogenesis and cytodifferentiation using both morphological and molecular criteria. 2. To determine the requirements for En 1, Wnt7a and Lmx lb in eccrine gland and nail development by characterizing the alterations in morphology and marker gene expression patterns that occur in single and double loss-of-function mutants. 3. To determine at what stages in development En1 is required to promote eccrine gland formation and inhibit ectopic nail-like differentiation by abrogating En I gene function at different developmental stages using a conditional En 1 mutant allele. 4. To determine whether ectodermally expressed En1 is sufficient to direct eccrine gland development and to inhibit nail/hair development by ectopically expressing En 1 using retroviral vectors.